PURPOSE: Increasing evidence indicates that the microbiome may influence tumor growth and modulate the tumor microenvironment of gastrointestinal cancers. However, the role of oral bacteria in the development of esophageal squamous cell carcinoma (EsoSCC) has remained unclear. Herein, we investigated the relationship between the periodontal pathogen Porphyromonas gingivalis and EsoSCC. METHODS: To identify bacterial biomarkers associated with EsoSCC, we analyzed microbiomes in oral biofilms. The presence of P. gingivalis in esophageal tissues and relationships of P. gingivalis infection with clinicopathologic characteristics in 156 patients with EsoSCC were assessed using immunohistochemistry. The role of P. gingivalis infection in in vitro and in vivo EsoSCC progression was also assessed. RESULTS: Microbiota profiles in oral biofilms revealed that P. gingivalis abundance was associated with an increased risk of EsoSCC development. In total, 57% of patients with EsoSCC were found to be infected with P. gingivalis. The presence of P. gingivalis was found to be associated with advanced clinical stages and a poor prognosis. It was also found to be associated with an elevated esophageal cancer incidence in a 4-nitroquinoline 1-oxide-induced mouse model and with an increased xenograft tumor growth. P. gingivalis infection increased interleukin (IL)-6 production and it promoted epithelial-mesenchymal transition and the recruitment of myeloid-derived suppressor cells. Furthermore, inhibited IL-6 signaling attenuated the tumor-promoting effects of P. gingivalis in 4-nitroquinoline 1-oxide-treated mice and xenograft mouse models. CONCLUSIONS: Our data indicate that P. gingivalis may promote esophageal cancer development and progression. Direct targeting of P. gingivalis or concomitant IL-6 signaling may be a promising strategy to prevent and/or treat EsoSCC associated with P. gingivalis infection.